Occupational chemical exposures in pregnancy and fetal growth: evidence from the Born in Bradford Study

ObjectivesThis prospective birth cohort study evaluated the effect of occupational exposure to endocrine disrupting chemicals (EDC) during pregnancy on inadequate fetal growth as measured by small-for-gestational age (SGA) and inadequate fetal growth measured by percentage of optimal birth weight (POBW). The study also identified the maternal characteristics associated with an increased risk of exposure to EDC.MethodsWe studied 4142 pregnant women who were in paid employment during pregnancy and participated in a population-based, prospective 2007–2011 birth cohort study, the Born in Bradford Study, with an estimated participation of 80%. Job titles were coded at 26–28 weeks’ gestation at a 4-digit level according to 353 unit groups in the 2000 UK Standard Occupational Classification. They were then linked to expert judgment on exposure to each of ten EDC groups as assessed through a job exposure matrix (JEM). We performed generalized estimation equation modelling by a modified Poisson regression to assess the risk of POBW and SGA associated with an increased risk of chemical exposures.ResultsThe frequency of POBW<85 significantly increased for mothers exposed to pesticides [adjusted risk ratio (RR_adj) 3.72, 95% confidence interval (CI) 1.40–9.91] and phthalates (RR_adj 3.71, 95% CI 1.62–8.51). There was a 5-fold increase risk of SGA for mothers exposed to pesticides (RR_adj 5.45, 95% CI 1.59–18.62). Veterinary nurses and horticultural trades were most frequently associated with exposure to pesticides while hairdressers, beauticians, and printing machine minders were associated with phthalates.ConclusionMaternal occupational exposure to estimated concentrations of pesticides and phthalates is associated with impaired fetal growth.     

How to schedule night shift work in order to reduce health and safety risks

Objectives:This discussion paper aims to provide scientifically based recommendations on night shift schedules, including consecutive shifts, shift intervals and duration of shifts, which may reduce health and safety risks. Short-term physiological effects in terms of circadian disruption, inadequate sleep duration and quality, and fatigue were considered as possible links between night shift work and selected health and safety risks, namely, cancer, cardio-metabolic disease, injuries, and pregnancy-related outcomes.Method:In early 2020, 15 experienced shift work researchers participated in a workshop where they identified relevant scientific literature within their main research area.Results:Knowledge gaps and possible recommendations were discussed based on the current evidence. The consensus was that schedules which reduce circadian disruption may reduce cancer risk, particularly for breast cancer, and schedules that optimize sleep and reduce fatigue may reduce the occurrence of injuries. This is generally achieved with fewer consecutive night shifts, sufficient shift intervals, and shorter night shift duration.Conclusions:Based on the limited, existing literature, we recommend that in order to reduce the risk of injuries and possibly breast cancer, night shift schedules have: (i) ≤3 consecutive night shifts; (ii) shift intervals of ≥11 hours; and (iii) ≤9 hours shift duration. In special cases – eg, oil rigs and other isolated workplaces with better possibilities to adapt to daytime sleep – additional or other recommendations may apply. Finally, to reduce risk of miscarriage, pregnant women should not work more than one night shift in a week.     

Mutant KRAS is a druggable target for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial–mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.Pancreatic cancer is an aggressive disease that develops in a relatively symptom-free manner and in most cases, is already advanced at the time of diagnosis (1). It has one of the highest fatality rates of all cancers and is one of the leading causes of cancer-related deaths in the Western world (1, 2). Pancreatic ductal adenocarcinoma (PDA) is the most common pancreatic neoplasm, responsible for 95% of pancreatic cancer cases (3). Genetic alterations in the KRAS signaling pathway are involved in over 90% of pancreatic cancer cases (4–6). KRAS mutations were shown to be an early event in the development of pancreatic cancer (5, 7, 8).The most common KRAS mutation of the human pancreas adenocarcinoma is a gain-of-function substitution mutation of glycine at codon 12 to aspartate (G12D) (5, 9–11). Moreover, PDA cancer cell growth was shown to be dependent on the activity of the mutated KRAS (5, 11) and accordingly, silencing KRAS has proven effective in controlling pancreatic cell line proliferation (12). Here, we aimed to harness the advantages of siRNA technology as a therapeutic modality for pancreatic cancer.Parenteral controlled drug delivery systems are used to improve and advance the therapeutic effects of drug treatments by providing optimized local drug concentrations over prolonged periods of time, reduction of side effects, and cost reduction (13). A prominent method of controlling the release rate of a drug in a pharmaceutical dosage is to embed the active agent within a polymeric matrix (14, 15). The polymer must be biocompatible, and in the case of parenteral administration, preferably biodegradable, to avoid the need to remove empty remnants.In the present study, we exploited the slow-release characteristics of the biodegradable polymer matrix, which we named local drug eluter (LODER) for the treatment of solid tumors.     

The colon - the latest terrain for capsule endoscopy.

Colonoscopy is the gold standard for evaluating pathologies of the large bowel, including screening for colorectal cancer. The technological features of current colonoscopes have not progressed much in recent years except for improved image and video display. The technique requires intubation and insufflation of the colon which are operator-dependent and involve a learning curve. Colonoscopy is an invasive procedure whose overall risk of complications is approximately 0.3%, increasing to 2% when polypectomy is performed. The PillCam Colon capsule endoscope (Given Imaging Ltd., Yoqneam, Israel) was developed for use as a safe, minimally invasive, non-sedation requiring, patient-friendly modality to visualize the colon. Only the interpretation of findings requires expertise. PillCam capsule endoscopy could be an alternative approach to colonoscopy for screening large populations. We report the first clinical investigations of the safety, feasibility and performance of colon capsule endoscopy compared with standard colonoscopy.     

Use of oxygen cannulas in extremely low birthweight infants is associated with mucosal trauma and bleeding, and possibly with coagulase-negative staphylococcal sepsis.

OBJECTIVE: We studied the association between the use of oxygen cannulas (OCs) and (1) nasal bleeding and (2) coagulase-negative staphylococcal sepsis (CNSS). STUDY DESIGN: Review of care sheets, with chi(2) or sign-test group comparisons. RESULTS: Infants treated with OCs were suctioned more frequently (2.6 vs 1.3 times per day, p<0.001), and had more bloody nasal secretions (34.6% vs 4.6%, p<0.05) that increased with increasing OC days. By 10 days, 90% of infants had experienced bloody secretions.CNSS occurred less often in infants treated with oxyhoods than those on OC or CPAP (1 of 13, 8%, vs 10 of 44, 23%), but the difference was not significant. Eight of the 10 CNSS episodes clustered within 3 and 7 days of starting CPAP or cannula treatments. CONCLUSION: OC use in extremely low birthweight infants is associated with nasal mucosal injury and bleeding. Studies are needed to see if use of OCs is a risk factor for CNSS.